Summary Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R ...and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. Methods In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00924989. Findings Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days 95% CI 256–507 vs 356 days 249–556; hazard ratio 0·94 95% CI 0·61–1·44; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three 3% patients vs no patients in the placebo group), nausea (two 2% vs none), and hyperglycaemia (two 2% vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. Interpretation Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. Funding Astellas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose:
To develop and evaluate an automatic intensity-modulated radiation therapy (IMRT) program for cervical cancer, including a Convolution Neural Network (CNN)-based prediction model and an ...automated optimization strategy.
Methods:
A CNN deep learning model was trained to predict a patient-specify set of IMRT objectives based on overlap volume histograms (OVH) and high-quality plan of previous patients. A total of 140 cervical cancer patients were enrolled in this study, including 100 patients in the training set, 20 patients in the validation set and 20 patients in the testing set. The input of this model was OVH data and the output were values of IMRT plan objectives. For patients in the testing set, the set of planning objectives were predicted by the CNN model and used to automatically generate IMRT plans. Meanwhile, manual plans of these patients were generated by 1 beginner planner and 1 senior planner respectively. Finally, dose distribution, dosimetric parameters and planning time were analyzed. In addition, the 3 types of plans were blinded compared and ranked by an experienced oncologist.
Results:
There were almost no statistically differences among these 3 types of plans in target coverage and dose conformity. Dose homogeneity were slightly decreased while the average dose and parameters for most organs-at-risk (OARs) were decreased in automatic plans. Especially in comparison with manual plans by the beginner planner, V40 of bladder and rectum decreased 6.3% and 12.3%, while mean dose of rectum and marrow were 1.1 Gy and 1.8 Gy lower with automatic plans (either P < 0.017). In the blinded comparison, automatic plans were chosen as best plan in 14 cases.
Conclusions:
For cervical cancer, automatic IMRT plans optimized from the CNN generated objectives have superior dose sparing without compromising of target dose. It significantly reduced the planning time.
Abstract Introduction First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of advanced non–small-cell lung cancer (NSCLC) with EGFR -activating mutations ...improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. Patients and Methods We performed a randomized, double-blind, placebo-controlled phase 2 study of linsitinib, a dual IGF-1R and insulin receptor TKI, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR -mutation positive, advanced NSCLC. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival (PFS). Results After randomization of 88 patients (44 each arm), the trial was unblinded early due to inferiority in the linsitinib arm. Median PFS for linsitinib versus placebo group was 8.4 versus 12.4 months (HR 1.37, P = .29). Overall response rate (47.7% vs. 75.0%, P = .02) and disease control rate (77.3% vs. 95.5%, P = .03) were also inferior. While most adverse events (AEs) were ≤ grade 2, linsitinib plus erlotinib was associated with increased AEs that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
While patient-centered care is highly anticipated nowadays, investigation of consumers’ perceptions and expectations about pharmacist’s pharmaceutical care when providing over-the-counter (OTC) drugs ...is sparse. This article aimed to explore consumers’ perceptions regarding the pharmaceutical care that community pharmacists provide in relation to OTC drugs. Semistructured interviews were conducted with consumers recruited (N = 97) in Yinchuan City, China. The 4 main themes that emerged were expectations on pharmaceutical care, attitude toward pharmacist’s competence, experience of self-medication, and suggestions for improving pharmaceutical care. Most participants had high expectations on community pharmacists to recommend the right medicines, to advise them about the effective use of drug, to advise them about the safe use of drug, and to recommend economic drugs. However, their previous experiences at community pharmacy were far from satisfaction reportedly, leading to a general distrust in pharmacist’s certification and qualification, knowledge, communication skills, and attitude. As a result, the participants turned to self-medication based on their personal experiences, their relatives’ experiences, the information on drug label, and the information distributed in the mass media. Realizing the need to improve pharmaceutical care, the participants also made improvement suggestions specific to community pharmacist, community pharmacy, and the government.
Background The increasing incidence of invasive Candida infections (ICIs) in preterm infants in the neonatal intensive care unit (NICU) of Xinhua Hospital aroused our concern. We undertook a ...retrospective study to evaluate the efficacy of different preventive measures for ICI in preterm infants. Methods Preterm infants with gestational age (GA) <33 weeks admitted between 2010 and 2013 were divided into 3 groups according to the preventive measures applied in different periods: the control group (CG), fluconazole group (FG), and integrated measures group (IMG). We analyzed the incidence of ICI and distribution of fungal pathogens in these 3 groups, and also evaluated the efficiency of various measures in preventing ICIs in preterm infants. Results The study sample comprised 261 preterm infants born at <33 weeks GA, including 94 in the CG, 99 in the FG, and 68 in the IMG. The differences among the groups were not significant at baseline. ICI developed in 41 of the 261 infants (15.7%). The incidence of ICI varied significantly among the groups: 22.3% in the CG (21/94), 18.2% in the FG (18/99), and only 2.9% in the IMG (2/68) ( P = .003). ICI was less frequent in the IMG compared with the CG ( P <.001) and the FG ( P = .003). Conclusions The integrated measures approach is meaningful for the prevention of ICIs in preterm infants in NICUs with many patients but inadequate medical resources in some developing countries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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